Anti-sclerostin Antibody Research Articles

Update on the Comprehensive Approach to Fragility Fractures.

The prevention and treatment of fragility fractures continuously evolve. Adequate fracture care should involve treating the fracture itself and the underlying bone disease. Although effective treatments of osteoporosis are available, a large proportion of patients with fragility fractures are not prescribed antiosteoporotic medications after their injury. Recent advances in diagnostic tools, medications, and implementation of Fracture Liaison Services allow for more effective and comprehensive treatment or fragility fractures. In the Fracture Liaison Service model, a physician and physician extenders coordinate care. This includes a thorough medical and surgical history, metabolic bone disease laboratory testing, dual-energy x-ray absorptiometry screening, treatment, and long-term follow-up. Treatment options include nonpharmacologic treatment with calcium and vitamin D and antiresorptive and anabolic agents. Antiresorptive agents such as bisphosphonates and denosumab are first-line treatments for osteoporosis and anabolic agents such as teriparatide are effective in reducing bone density loss and have implications in fracture healing. In addition, new anabolic agents including antisclerostin antibodies and parathyroid hormone-related protein show promise as potential treatments to increase bone density.

Anabolic Therapy for the Treatment of Osteoporosis in Childhood.

Numerous forms of osteoporosis in childhood are characterized by low bone turnover (for example, osteoporosis due to neuromuscular disorders and glucocorticoid exposure). Anti-resorptive therapy, traditionally used to treat osteoporosis in the young, is associated with further reductions in bone turnover, raising concerns about the long-term safety and efficacy of such therapy. These observations have led to increasing interest in the role of anabolic therapy to treat pediatric osteoporosis. While growth hormone and androgens appears to be relatively weak anabolic modulators of bone mass, emerging therapies targeting bone formation pathways (anti-transforming growth factor beta antibody and anti-sclerostin antibody) hold considerable promise. Teriparatide remains an attractive option that merits formal study for patients post-epiphyseal fusion, although it must be considered that adult studies have shown its effect is blunted when administered following bisphosphonate therapy. Mechanical stimulation of bone through whole body vibration therapy appears to be much less effective than bisphosphonate therapy for treating osteoporosis in children. New anabolic therapies which target important pathways in skeletal metabolism merit further study in children, including their effects on fracture risk reduction and after treatment discontinuation.

Treatment with anti-Sclerostin antibody to stimulate mandibular bone formation.

Anti-Sclerostin antibody (Scl-Ab) is a promising new bone anabolic therapy. Although anti-Scl-Ab stimulates bone formation and repair in the appendicular and axial skeleton, its efficacy in the craniofacial skeleton is still poorly understood. Using an established model of Down syndrome-dependent bone deficiency, 10 Ts65Dn mice and 10 wild-type mice were treated weekly via i.v. tail vein injection with vehicle or anti-Sclerostin for 3 weeks and euthanized 1 week after. Wild-type mice treated with the anti-Scl-Ab had increased mandibular bone, trabecular thickness, and alveolar height compared with controls. Anti-Scl-Ab increased Ts65Dn mandibular bone parameters such that they were statistically indistinguishable from those in vehicle-treated wild-type mandibles. Treatment with anti-Scl-Ab significantly increased mandibular bone mass and alveolar height in wild type mice and normalized mandibular bone mass and alveolar height in Ts65Dn mice. The anti-Scl-Ab therapy represents a novel method for increasing mandibular bone formation.

Osteoporosis in Rheumatic Diseases: Anti-rheumatic Drugs and the Skeleton.

Osteoporosis in rheumatic diseases is a very well-known complication. Systemic inflammation results in both generalized and localized bone loss and erosions. Recently, increased knowledge of inflammatory process in rheumatic diseases has resulted in the development of potent inhibitors of the cytokines, the biologic DMARDs. These treatments reduce systemic inflammation and have some effect on the generalized and localized bone loss. Progression of bone erosion was slowed by TNF, IL-6 and IL-1 inhibitors, a JAK inhibitor, a CTLA4 agonist, and rituximab. Effects on bone mineral density varied between the biological DMARDs. Medications that are approved for the treatment of osteoporosis have been evaluated to prevent bone loss in rheumatic disease patients, including denosumab, cathepsin K, bisphosphonates, anti-sclerostin antibodies and parathyroid hormone (hPTH 1-34), and have some efficacy in both the prevention of systemic bone loss and reducing localized bone erosions. This article reviews the effects of biologic DMARDs on bone mass and erosions in patients with rheumatic diseases and trials of anti-osteoporotic medications in animal models and patients with rheumatic diseases.

Serum sclerostin in vascular calcification and clinical outcome in chronic kidney disease.

Sclerostin, a potent soluble inhibitor of the Wnt signalling pathway, is known to inhibit bone formation by suppressing osteocytes differentiation and function. Patients with chronic kidney disease have high levels of serum sclerostin. Sclerostin has been implicated in the pathogenesis of vascular calcification, which may promote the cardiovascular events of morbidity and mortality in chronic kidney disease patients. However, the role of sclerostin in vascular calcification and clinical prognosis in chronic kidney disease remains elusive. While some studies suggested a positive correlation between serum sclerostin and vascular calcification or clinical outcome, other studies showed no or even negative correlation between them. Small sample size, heterogeneity in enrolled patients, discrepancy in anatomical structure examined and differences in the applied assays may be responsible for the discrepant results. Nonetheless, anti-sclerostin antibodies may be a new therapeutic approach to increase bone mass and strength in chronic kidney disease. This review aims to have a better understanding of the relationship of serum sclerostin with vascular calcification and clinical outcome in chronic kidney disease patients, and propose the application of anti-sclerostin therapy in chronic kidney disease.

MANAGEMENT OF ENDOCRINE DISEASE: Novel anabolic treatments for osteoporosis.

Skeletal anabolic agents enhance bone formation, which is determined by the number and function of osteoblasts. Signals that influence the differentiation and function of cells of the osteoblast lineage play a role in the mechanism of action of anabolic agents in the skeleton. Wnts induce the differentiation of mesenchymal stem cells toward osteoblasts, and insulin-like growth factor I (IGF-I) enhances the function of mature osteoblasts. The activity of Wnt and IGF-I is controlled by proteins that bind to the growth factor or to its receptors. Sclerostin is a Wnt antagonist that binds to Wnt co-receptors and prevents Wnt signal activation. Teriparatide, a 1-34 amino terminal fragment of parathyroid hormone (PTH), and abaloparatide, a modified 1-34 amino terminal fragment of PTH-related peptide (PTHrp), induce IGF-I, increase bone mineral density (BMD), reduce the incidence of vertebral and non-vertebral fractures and are approved for the treatment of postmenopausal osteoporosis. Romosozumab, a humanized anti-sclerostin antibody, increases bone formation, decreases bone resorption, increases BMD and reduces the incidence of vertebral fractures. An increased incidence of cardiovascular events has been associated with romosozumab, which is yet to be approved for the treatment of osteoporosis. In conclusion, cell and molecular studies have formed the foundation for the development of new anabolic therapies for osteoporosis with proven efficacy on the incidence of new fractures.

Proteasome inhibitor bortezomib is a novel therapeutic agent for focal radiation-induced osteoporosis.

Bone atrophy and its related fragility fractures are frequent, late side effects of radiotherapy in cancer survivors and have a detrimental impact on their quality of life. In another study, we showed that parathyroid hormone 1-34 and anti-sclerostin antibody attenuates radiation-induced bone damage by accelerating DNA repair in osteoblasts. DNA damage responses are partially regulated by the ubiquitin proteasome pathway. In the current study, we examined whether proteasome inhibitors have similar bone-protective effects against radiation damage. MG132 treatment greatly reduced radiation-induced apoptosis in cultured osteoblastic cells. This survival effect was owing to accelerated DNA repair as revealed by γH2AX foci and comet assays and to the up-regulation of Ku70 and DNA-dependent protein kinase, catalytic subunit, essential DNA repair proteins in the nonhomologous end-joining pathway. Administration of bortezomib (Bzb) reversed the loss of trabecular bone structure and strength in mice at 4 wk after focal radiation. Histomorphometry revealed that Bzb significantly increased the number of osteoblasts and activity in the irradiated area and suppressed the number and activity of osteoclasts, regardless of irradiation. Two weeks of Bzb treatment accelerated DNA repair in bone-lining osteoblasts and thus promoted their survival. Meanwhile, it also inhibited bone marrow adiposity. Taken together, we demonstrate a novel role of proteasome inhibitors in treating radiation-induced osteoporosis.-Chandra, A., Wang, L., Young, T., Zhong, L., Tseng, W.-J., Levine, M. A., Cengel, K., Liu, X. S., Zhang, Y., Pignolo, R. J., Qin, L. Proteasome inhibitor bortezomib is a novel therapeutic agent for focal radiation-induced osteoporosis.

Sclerostin antibodies in osteoporosis: latest evidence and therapeutic potential.

Sclerostin is an osteocyte-derived glycoprotein that inhibits Wnt/β-catenin signaling and activation of osteoblast function, thereby inhibiting bone formation. It plays a vital role in the regulation of skeletal growth. In adults, sclerostin secretion is modulated by skeletal loading (increased secretion with immobilization; less with weight bearing) and by hormonal/cytokine actions on the osteocyte. Sclerostin deficiency syndromes in humans and animals are characterized by high bone mass of normal quality. In animal models of osteoporosis, inhibition of sclerostin by monoclonal antibodies induces osteoblast activity and new bone formation, normalizing bone mass and improving bone architecture and strength. In recently completed clinical trials, anti-sclerostin antibody therapy results in marked increases in bone mineral density and rapid and substantial reduction in fracture risk. This review will focus on these recent studies and anticipate the role of anti-sclerostin therapy in the management of patients with osteoporosis.

Inhibiting the osteocyte-specific protein sclerostin increases bone mass and fracture resistance in multiple myeloma

AbstractMultiple myeloma (MM) is a plasma cell cancer that develops in the skeleton causing profound bone destruction and fractures. The bone disease is mediated by increased osteoclastic bone resorption and suppressed bone formation. Bisphosphonates used for treatment inhibit bone resorption and prevent bone loss but fail to influence bone formation and do not replace lost bone, so patients continue to fracture. Stimulating bone formation to increase bone mass and fracture resistance is a priority; however, targeting tumor-derived modulators of bone formation has had limited success. Sclerostin is an osteocyte-specific Wnt antagonist that inhibits bone formation. We hypothesized that inhibiting sclerostin would prevent development of bone disease and increase resistance to fracture in MM. Sclerostin was expressed in osteocytes from bones from naive and myeloma-bearing mice. In contrast, sclerostin was not expressed by plasma cells from 630 patients with myeloma or 54 myeloma cell lines. Mice injected with 5TGM1-eGFP, 5T2MM, or MM1.S myeloma cells demonstrated significant bone loss, which was associated with a decrease in fracture resistance in the vertebrae. Treatment with anti-sclerostin antibody increased osteoblast numbers and bone formation rate but did not inhibit bone resorption or reduce tumor burden. Treatment with anti-sclerostin antibody prevented myeloma-induced bone loss, reduced osteolytic bone lesions, and increased fracture resistance. Treatment with anti-sclerostin antibody and zoledronic acid combined increased bone mass and fracture resistance when compared with treatment with zoledronic acid alone. This study defines a therapeutic strategy superior to the current standard of care that will reduce fractures for patients with MM.

Osteocyte-specific WNT1 regulates osteoblast function during bone homeostasis.

Mutations in WNT1 cause osteogenesis imperfecta (OI) and early-onset osteoporosis, identifying it as a key Wnt ligand in human bone homeostasis. However, how and where WNT1 acts in bone are unclear. To address this mechanism, we generated late-osteoblast-specific and osteocyte-specific WNT1 loss- and gain-of-function mouse models. Deletion of Wnt1 in osteocytes resulted in low bone mass with spontaneous fractures similar to that observed in OI patients. Conversely, Wnt1 overexpression from osteocytes stimulated bone formation by increasing osteoblast number and activity, which was due in part to activation of mTORC1 signaling. While antiresorptive therapy is the mainstay of OI treatment, it has limited efficacy in WNT1-related OI. In this study, anti-sclerostin antibody (Scl-Ab) treatment effectively improved bone mass and dramatically decreased fracture rate in swaying mice, a model of global Wnt1 loss. Collectively, our data suggest that WNT1-related OI and osteoporosis are caused in part by decreased mTORC1-dependent osteoblast function resulting from loss of WNT1 signaling in osteocytes. As such, this work identifies an anabolic function of osteocytes as a source of Wnt in bone development and homoeostasis, complementing their known function as targets of Wnt signaling in regulating osteoclastogenesis. Finally, this study suggests that Scl-Ab is an effective genotype-specific treatment option for WNT1-related OI and osteoporosis.

Recent advances in the management of osteoporosis.

There has been substantial progress in the management of patients with osteoporosis and the prevention of osteoporotic fractures. Currently available strong anti-resorptive agents are bisphosphonates and an anti-receptor activator of nuclear factor-kappa B ligand (RANKL) antibody, denosumab. Although bisphosphonates and denosumab both inhibit bone resorption and prevent vertebral and non-vertebral fractures, their mechanisms of action are different. Whereas bisphosphonates’ effects on bone mineral density and fracture peak around 3 to 5 years and become plateaued, those of denosumab are maintained for up to 10 years. There are differences in the modes of action of these two drugs. Bisphosphonates accumulate on the mineralized bone surface and are released by the acid environment under osteoclastic bone resorption, whereas denosumab is not accumulated on bone but directly binds RANKL and inhibits its binding to the receptor RANK. Thus, the reduction in denosumab concentration 4 to 6 months after injection may enable RANK to bind to RANKL, where it is highly expressed, such as in damaged bone regions. As anabolic agents, only teriparatide has been available for a long time, but abaloparatide, a synthetic analog of PTHrP(1–34), is currently under development. Because of the difference in the preferential binding conformations of PTH1 receptor between teriparatide and abaloparatide, the latter shows anabolic effects with fewer bone resorptive effects. Romosozumab, an anti-sclerostin antibody, inhibits the action of sclerostin, a canonical Wnt signal inhibitor secreted from osteocytes, and enhances canonical Wnt signaling. Romosozumab robustly increases vertebral and proximal femoral bone mineral density within 12 months and inhibits vertebral and clinical fractures in patients with osteoporosis by enhancing bone formation and inhibiting bone resorption. In this review, we summarize the recent advances in therapeutic agents for the treatment of osteoporosis and discuss future prospects with their use.

Combination sclerostin antibody and zoledronic acid treatment outperforms either treatment alone in a mouse model of osteogenesis imperfecta

In this study, we examined the therapeutic potential of anti-Sclerostin Antibody (Scl-Ab) and bisphosphonate treatments for the bone fragility disorder Osteogenesis Imperfecta (OI). Mice with the Amish OI mutation (Col1a2 G610C mice) and control wild type littermates (WT) were treated from week 5 to week 9 of life with (1) saline (control), (2) zoledronic acid given 0.025mg/kg s.c. weekly (ZA), (3) Scl-Ab given 50mg/kg IV weekly (Scl-Ab), or (4) a combination of both (Scl-Ab/ZA). Functional outcomes were prioritized and included bone mineral density (BMD), bone microarchitecture, long bone bending strength, and vertebral compression strength. By dual-energy absorptiometry, Scl-Ab treatment alone had no effect on tibial BMD, while ZA and Scl-Ab/ZA significantly enhanced BMD by week 4 (+16% and +27% respectively, P<0.05). Scl-Ab/ZA treatment also led to increases in cortical thickness and tissue mineral density, and restored the tibial 4-point bending strength to that of control WT mice. In the spine, all treatments increased compression strength over controls, but only the combined group reached the strength of WT controls. Scl-Ab showed greater anabolic effects in the trabecular bone than in cortical bone. In summary, the Scl-Ab/ZA intervention was superior to either treatment alone in this OI mouse model, however further studies are required to establish its efficacy in other preclinical and clinical scenarios.

Anti-sclerostin antibodies for the treatment of osteoporosis

Anti-sclerostin antibodies for the treatment of osteoporosis

Clinical utility of anti-sclerostin antibodies

Based on a platform of strong preclinical data, several studies in humans have demonstrated that inhibiting sclerostin with specific antibodies results in a brisk albeit transient anabolic response in the skeleton without an accompanying increase in bone resorption. Impressive increases in bone mineral density and bone strength have been demonstrated. Other than mild injection site reactions, therapy for up to 2years has been well tolerated. The restriction of sclerostin expression almost exclusively to skeletal tissues, coupled with the absence of recognized medical problems in patients with heterozygous sclerostin deficiency, provides promise that the drug can be used safely. Recent results from a Phase 3 fracture trial suggest that anti-sclerostin therapy will be a useful and welcomed new treatment for patients with severe osteoporosis in need of skeletal reconstruction.

Sclerostin expression and functions beyond the osteocyte

Sclerostin, the product of the SOST gene, is a secreted inhibitor of Wnt signaling that is produced by osteocytes to regulate bone formation. While it is often considered an osteocyte-specific protein, SOST expression has been reported in numerous other cell types, including hypertrophic chondrocytes and cementocytes. Of interest, SOST/sclerostin expression is altered in certain pathogenic conditions, including osteoarthritis and rheumatic joint disease, and it is unclear whether sclerostin plays a protective role or whether sclerostin may mediate disease pathogenesis. Therefore, as anti-sclerostin antibodies are being developed for the treatment of osteoporosis, it is important to understand the functions of sclerostin beyond the regulation of bone formation.

The sclerostin-neutralizing antibody AbD09097 recognizes an epitope adjacent to sclerostin's binding site for the Wnt co-receptor LRP6.

The glycoprotein sclerostin has been identified as a negative regulator of bone growth. It exerts its function by interacting with the Wnt co-receptor LRP5/6, blocks the binding of Wnt factors and thereby inhibits Wnt signalling. Neutralizing anti-sclerostin antibodies are able to restore Wnt activity and enhance bone growth thereby presenting a new osteoanabolic therapy approach for diseases such as osteoporosis. We have generated various Fab antibodies against human and murine sclerostin using a phage display set-up. Biochemical analyses have identified one Fab developed against murine sclerostin, AbD09097 that efficiently neutralizes sclerostin's Wnt inhibitory activity. In vitro interaction analysis using sclerostin variants revealed that this neutralizing Fab binds to sclerostin's flexible second loop, which has been shown to harbour the LRP5/6 binding motif. Affinity maturation was then applied to AbD09097, providing a set of improved neutralizing Fab antibodies which particularly bind human sclerostin with enhanced affinity. Determining the crystal structure of AbD09097 provides first insights into how this antibody might recognize and neutralize sclerostin. Together with the structure–function relationship derived from affinity maturation these new data will foster the rational design of new and highly efficient anti-sclerostin antibodies for the therapy of bone loss diseases such as osteoporosis.

Bone Biomechanics and Bone Quality: Effects of Pharmaceutical Agents Used to Treat Osteoporosis

The biomechanical properties of bone define skeletal fragility. Surrogates such as bone density or biochemical markers are used to estimate the mechanical properties of bone because mechanical properties cannot be measured in a clinical environment. Within the set of bone’s mechanical properties, the material properties of the tissue itself are the defining feature of bone quality. Because they are the summation of all bone quality characteristics, bone’s material properties can define whether bone is fragile or healthy, even though other studies are required to determine the exact characteristics of microarchitecture, microdamage, and tissue physical properties that make the bone more or less fragile. For these reasons, measurement of the mechanical properties of bone is critical to assess bone health following drug treatments meant to ameliorate low bone mass, and are a common outcome measure in preclinical studies that assess the potential of these medications. This review describes the effects of existing anti-catabolic (bisphosphonates, SERMS, RANKL inhibitors) and anabolic (rhPTH (1-34) agents used to treat osteoporosis, and also several emerging potential therapies (cathepsin K inhibitors, anti-sclerostin antibody), on bone’s structural and material mechanical properties.

Osteoporosis treatment: bisphosphonates reign to continue for a few more years, at least?

The findings of the Women's Health Initiative study in 2002 marginalized the use of hormone replacement therapy and established bisphosphonates as the first line of treatment for osteoporosis. Denosumab could be used in selected patients. Although bisphosphonates only maintain the structure of bone complete with any accumulated structural or material faults, their bone selectivity and effectiveness in reducing the risk of fractures, together with their low cost, have left little room for improvement for new antiresorptives. The osteoanabolic teriparatide increases new bone formation, but it is administered for up to 2 years only and the cost remains a consideration. Similar restrictions are expected to apply to an anti-sclerostin antibody, which could be evaluated by the U.S. Food and Drug Administration in the near future. Cathepsin K-inhibiting antibody could be an alternative if approved; although an antiresorptive, it maintains bone formation, in contrast with bisphosphonates, and can be probably used for long-term treatment. Rare adverse effects of bisphosphonates, namely osteonecrosis of the jaws and atypical femoral fractures, have been disproportionally emphasized relative to their benefits/harm ratio. Treatment of osteoporosis is a long process, and many patients will require treatment with more than one type of drug over their lifetime.

Amgen/UCB build on bone franchise with anti-sclerostin antibody.

Amgen/UCB build on bone franchise with anti-sclerostin antibody.

Role of sclerostin in the pathogenesis of chronic kidney disease-mineral bone disorder

Sclerostin is a 190-amino-acid glycoprotein that is mainly secreted by osteocytes, and it decreases bone formation by inhibiting the terminal differentiation of osteoblasts and promoting their apoptosis. Sclerostin blocks the Wnt signaling pathway in osteoblasts by binding to low-density lipoprotein receptor-related protein 5/6 (LRP-5/6) receptors. We reviewed the literature detailing the role of sclerostin in the pathogenesis of chronic kidney disease-bone mineral disorder (CKD-MBD). Increased serum sclerostin levels may be correlated with increased serum levels of phosphate and fibroblast growth factor 23 (FGF23) in hemodialysis patients with relatively low parathyroid hormone levels. Decreased Wnt/β-catenin signaling occurs regardless of the overall changes in bone formation rates, suggesting that a reduction in the anabolic response may be a common feature of renal bone disorders; however, additional mechanisms may contribute to the diversity of osteodystrophy phenotypes. Recent clinical studies demonstrated that treatment with anti-sclerostin antibodies improved bone quality in the context of low but not high turnover renal osteodystrophy. Sclerostin also appears in the circulation, suggesting that it plays additional roles outside the skeleton under normal conditions and in disease states. The serum sclerostin levels in CKD patients are several times higher than in healthy subjects. Recent data suggest that the higher serum sclerostin levels are associated with increased fracture rates, but the relationship between sclerostin and cardiovascular disease is unclear. CKD stage-specific epidemiologic studies are needed to assess whether sclerostin elevations affect comorbidities associated with CKD-MBD.